© Prentice Hall 2001Chapter 91 Substitution Reactions S N 1 mechanism: C–X bond breaks first without any help from nucleophile This is a two-step process

© Prentice Hall 2001Chapter 92 On Line Course Evaluation for Chemistry 350/Section We are participating in the online course evaluation Please log on Click on Spring 2003 Evaluation That will take you to Dinput.asp Dinput.asp Your password is your address

© Prentice Hall 2001Chapter 93 Substitution Reactions Both mechanisms are called a nucleophilic substitution Which one takes place depends on the structure of the alkyl halide the reactivity and structure of the nucleophile the concentration of the nucleophile, and the solvent in which reaction is carried out

© Prentice Hall 2001Chapter 94 The S N 1 Reaction The mechanism of the S N 1 reaction involves two steps

© Prentice Hall 2001Chapter 95 The S N 1 Reaction

© Prentice Hall 2001Chapter 96 The S N 1 Reaction

© Prentice Hall 2001Chapter 97 The S N 1 Reaction The S N 1 reaction leads to a mixture of stereoisomers

© Prentice Hall 2001Chapter 98 The S N 1 Reaction: Factors Affecting the Rate increasing reactivity RI > RBr > RCl > RF Two factors affect the rate of formation of the carbocation ease with which the leaving group leaves stability of the carbocation increasing reactivity 3 o alkyl halide > 2 o alkyl halide > 1 o alkyl halide

© Prentice Hall 2001Chapter 99 The S N 1 Reaction: Carbocation Rearrangements

© Prentice Hall 2001Chapter 910 Stereochemistry of S N 2 and S N 1 Reactions inverted product ~50 -70% retained configuration ~ %

© Prentice Hall 2001Chapter 911 Stereochemistry of S N 2 and S N 1 Reactions

© Prentice Hall 2001Chapter 912 Competition Between S N 2 and S N 1 Reactions

© Prentice Hall 2001Chapter 913 Competition Between S N 2 and S N 1 Reactions TABLE 9.6 Summary of the Reactivity of Alkyl Halides in Nucleophilic Substitution Reactions methyl & 1 o alkyl halides S N 2 only 2 o alkyl halides S N 2 & S N 1 3 o alkyl halidesS N 1 only benzylic & allylic halides S N 2 & S N 1 vinylic & aryl halides neither S N 2 & S N 1 3 o benzylic & allylic halides S N 1 only

© Prentice Hall 2001Chapter 914 Competition Between S N 2 and S N 1 Reactions What are the factors that determine which mechanism operates? What are the factors that determine which mechanism operates? concentration of the nucleophile concentration of the nucleophile reactivity of the nucleophile reactivity of the nucleophile solvent in which the reaction is carried out solvent in which the reaction is carried out For S N 2rate = k 2 [alkyl halide][nucleophile] For S N 1rate = k 1 [alkyl halide]

© Prentice Hall 2001Chapter 915 Competition Between S N 2 and S N 1 Reactions Rate = k 2 [alkyl halide][nucleophile] + k 1 [alkyl halide] An increase in the concentration of the nucleophile increases the rate of the S N 2 reaction but has no effect on rate of S N 1 reaction

© Prentice Hall 2001Chapter 916 Competition Between S N 2 and S N 1 Reactions Rate = k 2 [alkyl halide][nucleophile] + k 1 [alkyl halide] An increase in reactivity of the nucleophile increases the rate of the S N 2 reaction by increasing the value of the rate constant, k 2 but has no effect on rate of S N 1 reaction because its rate is controlled by the slow ionization step, not by the fast reaction with the nucleophile

© Prentice Hall 2001Chapter 917 Role of the Solvent The solvent in which a nucleophilic substitution reaction is carried out has an influence on whether the reaction proceeds via an S N 2 or an S N 1 mechanism Two important solvent aspects include solvent polarity whether it is protic or aprotic

© Prentice Hall 2001Chapter 918 Solvent Polarity The dielectric constant is a measure of how well the solvent can insulate opposite charges from each other

© Prentice Hall 2001Chapter 919 Role of the Solvent The interaction between a solvent and an ion is called solvation When an ion interacts with a polar solvent, charge is no longer localized solely on the ion Polar solvents have a high dielectric constant Water Alcohols Solvents having O–H or N–H bonds are called protic solvents

© Prentice Hall 2001Chapter 920 Role of the Solvent in S N 1 Reactions The first step in an S N 1 reaction is the ionization of the halide. Where does the energy come from to break the carbon– halide bond? Favorable interaction with solvent molecules as charge is becomes separated in the transition state An S N 1 reaction can take place only in a polar solvent

© Prentice Hall 2001Chapter 921 Role of the Solvent in S N 1 Reactions If charge on the transition state is greater than the charge on the reactants, a polar solvent will provide greater stability to the transition state than to the reactants The result is a decrease in the  G ‡ of the reaction and a faster reaction

© Prentice Hall 2001Chapter 922 Role of the Solvent in S N 1 Reactions

© Prentice Hall 2001Chapter 923 S N 1 Reaction: Effect of Solvent Since charge is greater on the transition state, increasing the polarity of the solvent will increase the rate of the S N 1 reaction

© Prentice Hall 2001Chapter 924 S N 2 Reaction: Effect of Solvent Most S N 2 reactions involve a neutral alkyl halide and a charged nucleophile Consequently a polar solvent stabilizes the nucleophile more than the transition state Increasing the polarity of the solvent slows such an S N 2 reaction The nucleophiles used in S N 2 reactions however are generally insoluble in nonpolar solvents - some solvent polarity is needed

© Prentice Hall 2001Chapter 925 Competition Between S N 2 and S N 1 Reactions S N 2 and S N 1 : When a halide can undergo both an S N 2 and S N 1 reaction: S N 2 will be favored by a high concentration of a good (negatively charged) nucleophile S N 2 will be favored by a high concentration of a good (negatively charged) nucleophile S N 2 will be favored in a polar aprotic solvent S N 2 will be favored in a polar aprotic solvent S N 1 will be favored by a poor (neutral) nucleophile in a polar protic solvent S N 1 will be favored by a poor (neutral) nucleophile in a polar protic solvent

© Prentice Hall 2001Chapter 926 Biological Methylating Reactions If we wanted to add a methyl group to a nucleophile, methyl iodide might be used because iodide is the best leaving group

© Prentice Hall 2001Chapter 927 Biological Methylating Reactions Within a cell, methyl iodide cannot be used because of solubility limitations Instead, S-adenosylmethionine (SAM) and N 5 -methyltetrahydrofolate are used

© Prentice Hall 2001Chapter 928 Biological Methylating Reactions SAM is used in biological systems to convert norepinephrine (noradrenaline) into epinephrine (adrenaline) This is a simple methylation reaction

© Prentice Hall 2001Chapter 929 Biological Methylating Reactions